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Human-specific lncRNA TMEM9B-AS1 is downregulated in skeletal muscle of individuals with type 2 diabetes and regulates ribosomal biogenesis

Sen, I.; Smith, J. A. B.; Caria, E.; Savikj, M.; Lian, K.; Ellefsen, S.; Zierath, J. R.; Krook, A.

2024-07-06 cell biology
10.1101/2024.07.05.602204 bioRxiv
Show abstract

Long non-coding RNAs (lncRNAs) are important regulators of skeletal muscle physiology, with altered expression noted in several human diseases including type 2 diabetes. Here we report TMEM9B-AS1, a previously uncharacterized lncRNA, is downregulated in skeletal muscle of men with type 2 diabetes. Silencing of TMEM9B-AS1 in primary human myotubes attenuated protein synthesis, concomitant with reduced phosphorylation of ribosomal protein S6, a downstream target of ERK and mTOR pathways. Moreover, we provide evidence that TMEM9B-AS1 plays a pivotal role in the regulation of ribosomal biogenesis by facilitating mRNA stabilization of the transcription factor MYC through a direct physical interaction with the RNA-binding protein IGF2BP1. Disrupted ribosomal biogenesis resulting from TMEM9B-AS1 silencing is linked reduced skeletal muscle mass in type 2 diabetes, elucidating molecular mechanisms contributing to skeletal muscle loss in metabolic disease.

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